A new locus for X-linked dominant charcot-marie-tooth disease (CMTX6) is caused by mutations in the pyruvate dehydrogenase kinase isoenzyme 3 (PDK3) gene

Marina L. Kennerson, Eppie M. Yiu, David T. Chuang, Aditi Kidambi, Shih Chia Tso, Carolyn Ly, Rabia Chaudhry, Alexander P. Drew, Gary Rance, Martin B. Delatycki, Stephan L Zuchner, Monique M. Ryan, Garth A. Nicholson

Research output: Contribution to journalArticle

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Abstract

Hereditary motor and sensory disorders of the peripheral nerve form one of the most common groups of human genetic diseases collectively called Charcot-Marie-Tooth (CMT) neuropathy. Using linkage analysis in a three generation kindred, we have mapped a new locus for X-linked dominant CMT to chromosome Xp22.11. A microsatellite scan of the X chromosome established significant linkage to several markers including DXS993 (Zmax = 3.16; θ = 0.05). Extended haplotype analysis refined the linkage region to a 1.43-Mb interval flanked by markers DXS7110 and DXS8027. Whole exome sequencing identified a missense mutation c.G473A (p.R158H) in the pyruvate dehydrogenase kinase isoenzyme 3 (PDK3) gene. The change localized within the 1.43-Mb linkage interval, segregated with the affected phenotype and was excluded in ethnically matched control chromosomes. PDK3 is one of the four isoenzymes regulating the pyruvate dehydrogenase complex (PDC), by reversible phosphorylation, and is a nuclear-coded protein located in the mitochondrial matrix. PDC catalyzes the oxidative decarboxylation of pyruvate to acetyl CoA and is a key enzyme linking glycolysis to the energy-producing Krebs cycle and lipogenic pathways. We found that the R158H mutation confers enzyme hyperactivity and binds with stronger affinity than the wild-type to the inner-lipoyl (L2) domain of the E2p chain of PDC. Our findings suggest a reduced pyruvate flux due to R158H mutant PDK3-mediated hyper-phosphorylation of the PDC as the underlying pathogenic cause of peripheral neuropathy. The results highlight an important causative link between peripheral nerve degeneration and an essential bioenergetic or biosynthetic pathway required for the maintenance of peripheral nerves.

Original languageEnglish
Article numberdds557
Pages (from-to)1404-1416
Number of pages13
JournalHuman Molecular Genetics
Volume22
Issue number7
DOIs
StatePublished - Apr 1 2013

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Pyruvate Dehydrogenase Complex
Charcot-Marie-Tooth Disease
Peripheral Nerves
Mutation
Pyruvic Acid
Genes
Tooth
Chromosomes
Sensation Disorders
Phosphorylation
Exome
Nerve Degeneration
Inborn Genetic Diseases
Acetyl Coenzyme A
Decarboxylation
Citric Acid Cycle
Biosynthetic Pathways
Medical Genetics
X Chromosome
Peripheral Nervous System Diseases

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

A new locus for X-linked dominant charcot-marie-tooth disease (CMTX6) is caused by mutations in the pyruvate dehydrogenase kinase isoenzyme 3 (PDK3) gene. / Kennerson, Marina L.; Yiu, Eppie M.; Chuang, David T.; Kidambi, Aditi; Tso, Shih Chia; Ly, Carolyn; Chaudhry, Rabia; Drew, Alexander P.; Rance, Gary; Delatycki, Martin B.; Zuchner, Stephan L; Ryan, Monique M.; Nicholson, Garth A.

In: Human Molecular Genetics, Vol. 22, No. 7, dds557, 01.04.2013, p. 1404-1416.

Research output: Contribution to journalArticle

Kennerson, ML, Yiu, EM, Chuang, DT, Kidambi, A, Tso, SC, Ly, C, Chaudhry, R, Drew, AP, Rance, G, Delatycki, MB, Zuchner, SL, Ryan, MM & Nicholson, GA 2013, 'A new locus for X-linked dominant charcot-marie-tooth disease (CMTX6) is caused by mutations in the pyruvate dehydrogenase kinase isoenzyme 3 (PDK3) gene', Human Molecular Genetics, vol. 22, no. 7, dds557, pp. 1404-1416. https://doi.org/10.1093/hmg/dds557
Kennerson, Marina L. ; Yiu, Eppie M. ; Chuang, David T. ; Kidambi, Aditi ; Tso, Shih Chia ; Ly, Carolyn ; Chaudhry, Rabia ; Drew, Alexander P. ; Rance, Gary ; Delatycki, Martin B. ; Zuchner, Stephan L ; Ryan, Monique M. ; Nicholson, Garth A. / A new locus for X-linked dominant charcot-marie-tooth disease (CMTX6) is caused by mutations in the pyruvate dehydrogenase kinase isoenzyme 3 (PDK3) gene. In: Human Molecular Genetics. 2013 ; Vol. 22, No. 7. pp. 1404-1416.
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abstract = "Hereditary motor and sensory disorders of the peripheral nerve form one of the most common groups of human genetic diseases collectively called Charcot-Marie-Tooth (CMT) neuropathy. Using linkage analysis in a three generation kindred, we have mapped a new locus for X-linked dominant CMT to chromosome Xp22.11. A microsatellite scan of the X chromosome established significant linkage to several markers including DXS993 (Zmax = 3.16; θ = 0.05). Extended haplotype analysis refined the linkage region to a 1.43-Mb interval flanked by markers DXS7110 and DXS8027. Whole exome sequencing identified a missense mutation c.G473A (p.R158H) in the pyruvate dehydrogenase kinase isoenzyme 3 (PDK3) gene. The change localized within the 1.43-Mb linkage interval, segregated with the affected phenotype and was excluded in ethnically matched control chromosomes. PDK3 is one of the four isoenzymes regulating the pyruvate dehydrogenase complex (PDC), by reversible phosphorylation, and is a nuclear-coded protein located in the mitochondrial matrix. PDC catalyzes the oxidative decarboxylation of pyruvate to acetyl CoA and is a key enzyme linking glycolysis to the energy-producing Krebs cycle and lipogenic pathways. We found that the R158H mutation confers enzyme hyperactivity and binds with stronger affinity than the wild-type to the inner-lipoyl (L2) domain of the E2p chain of PDC. Our findings suggest a reduced pyruvate flux due to R158H mutant PDK3-mediated hyper-phosphorylation of the PDC as the underlying pathogenic cause of peripheral neuropathy. The results highlight an important causative link between peripheral nerve degeneration and an essential bioenergetic or biosynthetic pathway required for the maintenance of peripheral nerves.",
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AU - Chuang, David T.

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AU - Tso, Shih Chia

AU - Ly, Carolyn

AU - Chaudhry, Rabia

AU - Drew, Alexander P.

AU - Rance, Gary

AU - Delatycki, Martin B.

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